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基于杭抑郁药靶点基因的生物网络与通路分析
Alternative TitleBiological network and pathway analyses based on antidepressant target genes
王维笑
Subtype硕士
Thesis Advisor王晶
2018-06
Degree Grantor中国科学院大学
Place of Conferral中国科学院心理研究所
Degree Name理学硕士
Degree Discipline健康心理学
Keyword抗抑郁药物 靶点基因 蛋白互作网络 功能通路
Abstract

抑郁症是一种常见的精神疾病,具有高患病率和高危害性。药物治疗是中重度抑郁患者的有效选择。抑郁症的越发普遍性与当前抗抑郁药物疗效的局限性,促使研究者更加深入地探索治疗药物作用背后的分子机制。而药物疗效的发挥不仅仅依赖于药物靶点,还依赖于其所参与的整个生物网络系统中其它分子的调控和彼此间的相互作用。因此,药物作用机制的探索与新药的研发不仅要聚焦于药物靶点本身,还要充分理解它们所涉及的生物网络和通路,及其之间错综复杂的相互作用。本研究基于蛋白互作网络和生物通路的分析策略,以抗抑郁药物靶点基因为核心展开了一系列研究,以期从系统角度更好地理解抗抑郁药物的作用途径,为揭示抗抑郁过程背后的机制提供线索和提示,并鉴定抗抑郁过程中的关键基因,为药物研发提供前期的理论支持。

本研究主要按照以下步骤展开:(1)通过药物靶点基因之间的直接相互作用网络分析和通路富集分析,获得枢纽基因,以及靶点基因参与的功能通路,为探索靶点基因如何协作发生作用提供提示。(2)通过构建靶点基因以及与其有相互作用的基因的间接相互作用网络,获得在靶点基因之间起关键作用的拓展基因,探索新的潜在药物靶点。同时通过通路富集分析,获得这些基因所参与的主要功能通路,以加深对抗抑郁过程的理解。(3)结合药物基因组学数据,寻找靶点基因、拓展基因与药效相关基因之间的关系,在此基础上对前两部分获得的功能通路进行比较分析,并结合相关文献研究,进一步探讨抗抑郁过程背后可能的作用途径。

本研究的主要结果如下:(1)通过数据库检索,共得到了52种抗抑郁药物及其对应的108个靶点基因。通过靶点基因直接相互作用网络及功能分析,获得了DRD4 , DRD2 , HRH3、GRM5、GABRG2、DRD1、GRIN1l和ADB2等枢纽基因;鉴定了当前抗抑郁药物靶点基因在体内发生作用的主要功能通路,如多巴胺受体参与的通路、YY氨基丁酸受体相关通路、’肾上腺素受体相关通路等。(2)通过靶点基因间接相互作用网络及功能分析,得到了与靶点基因有密切相互作用的569个拓展基因,并鉴定了抗抑郁过程中的多个关键基因,包括目前己经是药物靶点但还有待继续探索研究的基因,如GSK3B,MTNR1A和NTNR1B等;以及目前还不是药物靶点但具有潜在药靶价值的基因,如DLG4;发现了除单胺类受体、谷氨酸受体和GABA受体等相关的通路外,雌激素信号通路、感染与炎症等免疫系统相关通路在抗抑郁过程中也发挥了显著作用。(3)结合药物基因组学数据,得到了47个靶点基因与药效相关,25个拓展基因与药效相关,并发现这些拓展基因显著富集在抗原加工提呈、雌激素信号通路等免疫相关通路,这进一步说明了免疫系统在抗抑郁药物作用发挥中的重要地位。

本论文通过以上分析,揭示了抗抑郁药物潜在的免疫调节特征,并鉴定了抗抑郁过程中的多个关键基因。从通路与网络的角度为理解抗抑郁药物背后的作用途径提供了新思路,为新型抗抑郁药物的研发提供了新视角,同时也从药物作用层面为抑郁症病因学的免疫失衡假说提供了一定的理论支持。

Other Abstract

Depression is a common mental illness with high prevalence and harmfulness.Drug therapy is an effective choice for patients with moderate to severe depression. The increasing prevalence of depression and the limitations of current antidepressant medications have prompted researchers to further explore the molecular mechanisms underlying the effects of therapeutic drugs. The efficacy of drugs depends not only on drug targets, but also on the regulation and interaction of other molecules in the entire biological network system they are involved in. Therefore, the exploration of drug action mechanisms and the development of new drugs should not only focus on the drug targets themselves, but also fully understand the biological networks and pathways involved, and the intricate interactions between them. This study conducted a series of protein interaction networks and biological pathways analyses centering on antidepressant target genes to better understand the antidepressant action from a systematic perspective, to provide clues for revealing the mechanisms behind the antidepressant process, and to offer new candidate targets.

This study was mainly carried out in accordance with the following steps: (1) In order to explore how the target genes work together, direct interaction network analysis and pathway enrichment analysis between target genes were conducted. (2) To explore new candidate drug targets, an indirect interaction network with the target genes and the extended genes was constructed. At the same time, to understand the process of antidepressant effect, the major functional pathways involved in these genes were obtained through pathway enrichment analysis. (3) To find out the relationship among the target genes, the extended gene and the antidepressant efficacy-related genes by combining the pharmacogenoinics data, and then compare and deeply discuss the functional pathways obtained in the first two parts.

The main results of this study were as follows: (1) A total of 52 antidepressant drugs and their corresponding 108 target genes were obtained through database searching. Hub target genes, such as DRD4, DRD2, DRH3, GRM5,DRD1,GRIN1 and ADRR2 were obtained by the direct interaction network analysis of target genes. The main functional pathways of the current antidepressant target genus in vivo, such as the dopamine receptors rerated pathways, γ-aminobutyric acid receptor related pathways, and adrenergic receptor}related pathways, were identified by the functional analysis. (2) 569 extended genes were obtained thro ugh the indirect interaction network. Several key genes in the antidepressant process wore identified, including genes that were already drug targets but still need to continue exploring, such as GSK3B, MTNR1A, arid MTNR1B, and genes that are not yet drub targets but have Potential drug target Values, such as DLC4. By functional analysis, we found that in addition to traditional monoamine system-related pathways, the immune system-related pathways such as estrogen signaling, infection and inflammation pathways, also played a significant role in the anti-depression process. (3) Through combining pharmacogenomics data, 47 target genes end 25 extended genes were found to be related to the antidepressant efficacy, respectively The extended genes were found to be significantly enriched in immune-relevant pathways such as antigen processing and presentation and estrogen signaling pathways, further demonstrating the importance of the immune system in the role of anti-depression process.

Through the above analyses, ,this papa revealed the potential immune regulatory characteristics of antidepressants and identified several icy genes in the antidepressant process In general, this study provided new ideas for understanding the pathways behind the antidepressant process at systematic levels, and provided new perspectives for the development of new antidepressant drubs. Last but not least, this study provided theoretical support for the immune imbalance hypothesis of the etiology of depression from the view of drub action.

Pages64
Language中文
Document Type学位论文
Identifierhttp://ir.psych.ac.cn/handle/311026/28873
Collection健康与遗传心理学研究室
Recommended Citation
GB/T 7714
王维笑. 基于杭抑郁药靶点基因的生物网络与通路分析[D]. 中国科学院心理研究所. 中国科学院大学,2018.
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